The P substance is a natural undecapeptide from the Tachykinins family and is used for its rapid stimulant action on smooth muscle tissue. More specifically, the P substance is an active pharmacological neuropeptide that is produced in mammals. It was originally isolated in the intestine and possesses an amino acid sequence that has been described by D. F. Veber, in the patent U.S. Pat. No. 4,680,283. The implication of the P substance, like in other Tachykinins, is seen in the physiopathology in a large number of illnesses that are well demonstrated in the bibliography.
The P substance receptor is a member of the super family of G-protein-coupled receptors. The neuropeptide receptor of the P (NK-1) substance is well distributed in the nervous system of mammals (especially in the cerebrum and spinal cord) the circulatory system and in the peripheral tissues (especially in the duodenum and in the jejunum) and is involved in the regulation of diverse biological processes.
The central and peripheral action of the Tachykinins in mammals have been associated with various inflammatory conditions such as migraines, rheumatoid arthritis, asthma, and intestinal inflammatory disease, as well as in the mediation of nauseous reflexes, and the regulation of CNS central nervous system disorders such as Parkinson's disease. (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys.; 1997, 612-621) and depression (Science, 1998, 281, 1640-1645).
In the article titled “Tachykinin Receptor and Tachykinin Receptor Antagonists”, by J. Auton, in Pharmacol.; 1993, 13, 23-93, the use of antagonists of the P substance have been evidenced in the treatment of headaches, especially migraines, Alzheimer's disease, multiple sclerosis, attenuation of the syndrome in the absence of opiates, cardio vascular changes, edemas, such as those provoked by burns, in chronic inflammatory illnesses like rheumatoid arthritis, asthma, hyperactive bronchials, and other respiratory illnesses including allergic rhinitis, etc.
Also, U.S. Pat. No. 5,972,938 describes a method for the treatment of a psychoimmunological disorder or psychomotor by way of the administration of an NK1 receptor antagonist.
The article published in Nature, 2000,405 (6783), 180-183 details the activity in rats lacking NK-1 receptors and shows a decrease in the beneficial effects of morphine. Consequently, the NK-1 antagonist receptors can be used in the treatment of breaking certain drug addition habits such as those associated with opiates, nicotine as well as in the reduction of abuse and abstinence from the drugs.
The article in Life Sci.; 2000, 67(9), 985-1001 describes the Astrocytes express functional receptors for various neurotransmitters in the reception of the P substance. The cerebral tumors of malignant glials derived from Astrocytes unchain under the action of the Tachykinins mediating the NK-1 receptors in the secretion of soluble mediators that augment the speed of reproliferation. Consequently, the selective antagonists of NK-1 can be very useful therapeutic agents in the treatment of malignant gliomas and for the treatment of cancer.
Additionally, the New Journal of Medicine, 1999, 340, 190-195, states that the use of a selective NK1 receptor induces the reduction of vomiting by employing cisplatin.
In the article published in the International Journal of Cancer by Antal Orosz et al. 1995, 60, 82-87, the use of diverse peptide antagonists in the P substance (SP) is described in the inhibition of the proliferation of lung cancer cells. (Ex. in designated cells NCI-H69). Equally as important is the article published in Cancer Research, 1994, 54, 3602-3610, describing another antagonist of the SP as well as other peptides capable of the inhibition of the growth of various in-vitro lines in cancerous lung cells (ex. Designated cells NCI-H510, NCI-H345, and SHP-77).
The patent EP 773026 (Pfizer) states the use of non-peptide NK1 receptor antagonists in the treatment of breast cancer, particularly in the treatment of small lung cancers in APUdoma, neuro endocrinic tumors, and small extra lung carcinomas.
Additionally in the WO 2001001922 patent the use of NK1 receptors in the treatment of adenocarcinoma is described, most specifically in prostatic carcinomas. Giardina, G.; Gagliardi S. and Martinelli M. review the most recent patents about the NK1, NK2 and NK3 receptors in “Antagonists at the neurokinin receptors-Recent patent literature” (IDrugs 2003; 6 (8): 758-772). The authors describe the action of the molecules of the most important world producers with a specific indication of the most noteworthy possible applications being used in the treatment of: depression, inflammation, anxiety, vomiting, Ulcerative colitis and other illnesses.